Hippocampal adult neurogenesis has captured the attention of the neuroscience community because it highlights a previously unrecognized capacity for plasticity and regeneration within the adult brain. It is widely accepted that newly generated neurons integrate into the mature circuit and participate in hippocampal dependent behaviors. It is also well established that the proliferation and survival of adult generated neurons are tightly regulated by external stimuli such as exercise, environmental enrichment and stress. Thus neurogenesis provides a mechanism that links experiences with plasticity and regeneration of the adult neural circuit. Despite the extensive literature supporting experience-dependent regulation of neurogenesis, very little is known about how such regulation is achieved. The goal of this project is to elucidate, at the single cell and circuit level, how experience regulates neurogenesis by controlling the survival of newborn neurons. Although many newborn neurons are produced, only a fraction survives. We will test the hypothesis that the long-term fate of adult generated neurons is controlled by GABAergic synaptic input during a critical period of their maturation and that synaptic input is regulated in an experience dependent- manner. We will use transgenic methods to identify adult generated neurons at a specific developmental stage and electrophysiological techniques to assess their synaptic connectivity. In Specific Aim 1 & 2 we will establish how newborn neurons respond to network activity during their critical period for fate determination. In Specific Aim 3 we will determine how the synaptic input of newborn neurons is altered by experiential and genetic conditions that enhance survival. Then we will test the causal link between synaptic activity and neuron survival. These results will reveal how activity in specific components of the hippocampal circuit contributes to the survival of adult generated neurons, thereby allowing experience-dependent long-term modifications of the adult neural network. Impaired survival of adult generated neurons has been implicated in many neuropathological conditions including neurodegenerative diseases and psychiatric illnesses, thus these results will also provide insight into potential therapeutic targets to promote the survival of newborn neurons in disease states. PUBLIC HEALTH RELEVANCE: The goal of this project is to elucidate, at the single cell and circuit level, how experience regulates neurogenesis by controlling the survival of newborn neurons. Impaired survival of adult generated neurons has been implicated in many neuropathological conditions including neurodegenerative diseases and psychiatric illnesses, thus these results will also provide insight into potential therapeutic targets to promote the survival of newborn neurons in disease states.